Efficient and reliable iodination and o-Methylation of fluorinated phenols

Article abstract of DOI:10.1002/ejoc.201000161

Fluorinated phenols and other electron-deficient phenolic substrates are efficiently and cleanly iodinated by an iodine/ iodide mixture employing alkaline conditions. This protocol turned out to be the most practical for the generation of such highly fluorinated iodophenols. For later application in coupling processes the protection of the phenolic hydroxy moiety is often required. Therefore, a practical iodination and subsequent methylation sequence was elaborated providing the highly fluorinated anisoles with good to excellent yields. The developed method is applicable for a broad scope of fluorinated phenols and analogues.

Full text of DOI:10.1002/ejoc.201000161

FULL PAPER
DOI: 10.1002/ejoc.201000161
Efficient and Reliable Iodination and O-Methylation of Fluorinated Phenols
Robert Francke,[a] Gregor Schnakenburg,[b] and Siegfried R. Waldvogel*[a]
Keywords: Iodination / Phenols / Oxidation / Alkylation / Fluorinated compounds
Fluorinated phenols and other electron-deficient phenolic
substrates are efficiently and cleanly iodinated by an iodine/
iodide mixture employing alkaline conditions. This protocol
turned out to be the most practical for the generation of such
highly fluorinated iodophenols. For later application in cou-
pling processes the protection of the phenolic hydroxy
moiety is often required. Therefore, a practical iodination
and subsequent methylation sequence was elaborated pro-
viding the highly fluorinated anisoles with good to excellent
yields. The developed method is applicable for a broad scope
of fluorinated phenols and analogues.
actions.[17] The installation of iodo moieties in peptidic sub-
strates is cleanly performed by the Barluenga reagent.[18]
However, this powerful iodonium species has to be pre-
pared with mercury salts and is therefore not preferable for
larger applications.[19]
The installation of an iodo moiety in electron-deficient
phenols turned out to be difficult.[20] In particular, fluori-
nated substrates seem to be challenging since the electron-
withdrawing nature and good leaving-group properties of
fluorine cause side reactions.[21] Here we present a reliable
and efficient protocol for the iodination of fluorinated
phenols with simple iodination reagents.
Introduction
Iodo substituents offer the straightforward installation of
various functionalities because of their outstanding reactiv-
ity.[1] Consequently, iodoarenes represent very valuable pre-
cursors for the synthesis of complex organic molecules. For
example, transition-metal-catalyzed cross-coupling reac-
tions of arenes represent an extremely powerful synthetic
tool, wherein the iodo derivatives are usually considered as
the preferred substrates.[2] Furthermore, the superior leav-
ing nature of this specific functionality is beneficial in de-
halometallations,[3] protodeiodinations[4] and metal-cata-
lyzed homo-coupling reactions.[5] Among the latter, the
copper-mediated Ullmann coupling is the most prominent
transformation.[6] In addition, iodo-substituted aromatic
systems are applied as contrast agents for X-ray diagnos-
tics[7] or as radiolabelled compounds.[8] Fluoro substituents
are known to enhance the metabolic and electrochemical
stability.[9] Consequently, fluorinated compounds represent
the key entities for pharmaceutical[10] and energy-storage
applications.[11]
In general, phenols can be iodinated under basic or
slightly basic conditions.[12] Common protocols involve the
application of iodine/morpholine mixtures.[13] Alternatively,
iodine can be provided as dichloroiodate in combination
with organic cations[14] or as iodo amide in ionic liquids.[15]
The reagent mixtures consisting of hypochlorite and iodide
give direct access to simple iodophenols.[16] Treatment with
iodine monochloride is mostly applied for periodination re-
Results and Discussion
First tests for the iodination of some fluorinated phenols
with several iodination reagents resulted in very low yields
with a tremendously impure product or very slow conver-
sion with many byproducts. In particular the conversion of
1m with BnNEt3ICl2/NaHCO3 lead to a yield of 31% (GC)
in a very complex mixture, which was hardly separated. The
use of iodine monochloride for the iodination of 1m re-
vealed even poorer results, namely a yield of 15% (GC),
whereas the 6-chlorinated phenol was identified as the main
product (GC/MS). The iodinated phenol 2m was isolated
in moderate yields (36%) after conversion of 1m with I2/
morpholine. However, these reaction conditions are not ap-
plicable to more electron-deficient substrates, as the reac-
tion of 1a was very slow and aborted after 5 d (69% starting
material, 31% product, GC). Treatment at elevated tem-
perature rendered led to complete decomposition of the
substrate. Consequently, a more drastic but still practical
and environmentally benign method for the iodination of
fluorinated phenols was desired. For this purpose the use
of an aqueous iodine/iodide mixture in presence of NaOH
(Scheme 1) proved to be the most convenient way.
[a] Kekulé Institute for Organic Chemistry and Biochemistry
Bonn University, Gerhard-Domagk-Strasse 1, 53121 Bonn,
Germany
Fax: +49-228-73-9608
E-mail: waldvogel@uni-bonn.de
[b] X-ray Analysis Department, Institute for Inorganic Chemistry
Bonn University, Gerhard-Domagk-Strasse 1, 53121 Bonn,
Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000161.
Eur. J. Org. Chem. 2010, 2357–2362
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R. Francke, G. Schnakenburg, S. R. Waldvogel
FULL PAPER
Table 1. Synthesis of iodinated phenols and corresponding anisoles.
Scheme 1. Conversion of electron-deficient phenols to the corre-
sponding iodinated anisoles (R = F, Cl, Br, NO2).
First, the installation of iodo moieties into difluorophen-
ols was studied. 2,4-Difluorophenol (1a) was iodinated in
position 6 in 66% yield. Subsequent methylation in the
combined sequence provided 2,4-difluoro-6-iodoanisole in
almost the same yield (Table 1, Entry 1). The isomeric di-
fluorophenols result in the iodination reaction in consider-
ably better yields. Iodination in position 4 provided the
iodinated phenol 2b in excellent yield, whereas the anisole
derivative was obtained in 86% isolated yield (Entry 2). 3,4-
Difluorophenol offers two positions for the installation of
iodo groups. When applying only 1 equiv. of the iodination
mixture to 1c, the functionalization occurs on the less hin-
dered position 6, and the corresponding phenol 2c and ani-
sole 3c were isolated in 88% and 84% yield, respectively.
A clean twofold installation ortho to the hydroxy group is
achieved by treatment with 3 equiv. of the iodination mix-
ture (Entry 4). Substrates exhibiting three fluoro groups in
positions 3, 4 and 5 represent suitable substrates for the
mono- and difunctionalization by altering the amount of
the iodination reagent mixture. The corresponding anisoles
are isolated in almost the same yield as the intermediate
phenols (Entries 5 and 6). Analogous substrates involving
bromo and fluoro moieties can be transformed to the iodo
derivatives 2g and 3g in 90% and 87% isolated yields,
respectively (Entry 7). Exchange of halogen substituents
was not observed under the applied reaction conditions.
The dichloro analogue 1h as well as the chloro/fluoro-sub-
stituted substrates 1i and 1j are superb starting materials
for these transformations (Entries 8–10). A chloro moiety
in position 4 gives excellent yields, whereas a fluoro substit-
uent in that particular position leads to slightly depressed
yields in the iodination process (Entry 9). Phenols with a
fluoro moiety in para position tend to give 4,4-disubstituted
cyclohexadienones upon oxidative treatment,[22] which are
prone to decomposition under the given reaction condi-
tions. These side products were not isolated, but might re-
duce the yields during the iodination process. Employment
of 2,3,4-trifluorophenol provides the 6-iodinated phenol 2k
and the corresponding anisole 3k in 95% and 90% isolated
yield, respectively (Entry 11).
[a] Yield after both steps, without purification after first step. [b]
1 equiv. I2, 1 equiv. KI, stirred at 0 °C for 2 h. [c] 3 equiv. I2,
3 equiv. KI. [d] 2 equiv. I2, 2 equiv. KI, stirred at 85 °C for 8 h. [e]
Stirred for 3 d, *16% of recovered starting material, 8% of diiodin-
ated product. [f] Solvent mixture: MeOH/H2O (1:1), dissolved I2
(1.05 equiv.) and KI (1.05 equiv.) were added slowly.
of the hydroxy functionality occurs to the adjacent nitro
Replacement of a fluoro moiety by a nitro functionality moiety and not to the competing fluoro group (Figure 1).
still allows the installation of an iodo group on a remaining However, by this arrangement the nitro moiety is brought
activated position. For excellent to good yields the conver- into the plane of the aromatic core and consequently a
sion requires harsher reaction conditions and prolonged dense layer-type packing is possible in the solid state.
treatment (Entry 12).
Analogous conversion of 4-fluoro-2-methylphenol (1m)
The installation of the iodo moiety in position 4 of prod- was less successful under the previously described condi-
uct 2l was verified by an X-ray analysis of a suitable single tions. Mostly decomposition was observed. Switching to
crystal. Interestingly, the intramolecular hydrogen bonding aqueous methanol as reaction medium and a slow addition
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Iodination and O-Methylation of Fluorinated Phenols
with water and dried (MgSO4). After removal of the solvent under
reduced pressure, the crude product was purified either by column
chromatography or short-path distillation, depending on the ani-
sole.
2,4-Difluoro-6-iodophenol (2a): 2,4-Difluorophenol (1.02 g,
7.84 mmol), purified by column chromatography (cyclohexane/
ethyl acetate, 4:1, RF = 0.46), yielded 2a (1.32 g, 5.17 mmol, 66%);
1
m.p. 48 °C. H NMR (300 MHz, [D6]DMSO): δ = 10.31 (br. s, 1
Figure 1. Molecular structure of 2l by X-ray analysis of a single
H, OH), 7.43 (ddd, J = 7.9, 3.0, 2.0 Hz, 1 H), 7.28 (ddd, J = 10.9,
8.7, 3.0 Hz, 1 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 154.7
(dd, J = 241.6, 11.4 Hz), 149.5 (dd, J = 245.6, 13.0 Hz), 141.8 (dd,
J = 15.4, 3.5 Hz), 120.3 (dd, J = 24.2, 3.7 Hz), 104.8 (dd, J = 27.0,
23.7 Hz), 86.83 (dd, J = 10.2, 2.6 Hz) ppm. 19F NMR (282 MHz,
crystal.
of iodination reagent mixture led to synthetically acceptable
amounts for 2m and 3m in 64% and 55% isolated yields,
respectively (Entry 13).
[D6]DMSO):
δ = –117.29, –122.61 ppm. HRMS: calcd. for
The limit of the method is reached when electron-rich C6H3F2IO 255.9197; foun: 255.9198. C6H3F2IO (255.99): calcd. C
28.15, H 1.18; found C 28.17, H 1.33.
fluorophenols such as 4-fluoroguajacol are subjected to the
reaction conditions. Only a dark residue was obtained with-
out any indication of the desired product.
2,4-Difluoro-6-iodoanisole (3a): 2,4-Difluorophenol (1a) (2.08 g,
15.99 mmol), purified by column chromatography (cyclohexane, RF
= 0.43) yielded 3a as a colorless liquid (2.59 g, 9.59 mmol, 60%).
1H NMR (300 MHz, CDCl3): δ = 7.27 (ddd, J = 10.9, 8.2, 3.0 Hz,
1 H), 6.86 (ddd, J = 7.4, 3.0, 2.1 Hz, 1 H), 3.86 (d, J = 1.1 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = = 158.4 (dd, J = 249.1,
11.6 Hz), 154.4 (dd, J = 254.0, 12.7 Hz), 144.9 (dd, J = 12.5,
Conclusions
Fluorinated and other electron-deficient phenols are ef-
ficiently iodinated by an I2/I– mixture in alkaline media. 4.2 Hz), 121.2 (dd, J = 24.5, 3.8 Hz), 105.9 (dd, J = 26.4, 22.4 Hz),
91.4 (dd, J = 10.4, 2.7 Hz), 61.7 (dd, J = 4.6, 1.1 Hz) ppm. 19F
The employed reagents for iodination are readily available
and environmentally benign. The selectivity for mono- vs.
multiple-iodination can be directed by the amount of ap-
plied iodination reagent. The elaborated protocol is the best
way to iodinate fluorinated phenols and can be reliably used
to prepare larger amounts. For the preparation of anisoles
a telescoped reaction sequence provides similar yields with-
out a purification of the intermediate iodinated phenols.
NMR (282 MHz, CDCl3): δ = –115.7, 123.05 ppm. HRMS: calcd.
for C7H5F2IO 269.9353; found 269.9351. C7H5F2IO (270.02):
calcd. C 31.14, H 1.87; found C 31.05, H 1.86.
2,6-Difluoro-4-iodophenol (2b): 2,6-Difluorophenol (1b) (1.00 g,
7.69 mmol), purified by sublimation (65 °C, 4 mbar), yielded 2b as
a colorless solid (1.83 g, 7.15 mmol, 93%); m.p. 56–57 °C. 1H
NMR (300 MHz, [D6]DMSO): δ = 10.47 (br. s, 1 H, OH), 7.49–
7.35 (m, 2 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 152.5
The use of these building blocks in the synthesis of materi-
als for energy-storage devices will be reported in due course.
(dd, J = 246.8, 7,1 Hz), 134.14 (t, J = 15.8 Hz), 120.8 (dt, J = 12.1,
3.2 Hz), 77.8 (t, J = 9.3 Hz) ppm. 19F NMR (282 MHz, [D6]-
DMSO): δ = –130.45 ppm. HRMS: calcd. for C6H3F2IO 255.9197;
found 255.9191. C6H3F2IO (255.99): calcd. C 28.15, H 1.18; found
C 27.88, H 1.26.
Experimental Section
2,6-Difluoro-4-iodoanisole (3b): 2,6-Difluorophenol (1b) (0.51 g,
3.92 mmol), purified by short-path distillation (55 °C, 2 mbar)
yielded 3b as a colorless liquid (0.91 g, 3.37 mmol, 86%). 1H NMR
(300 MHz, [D6]DMSO): δ = 7.42–7.60 (m, 2 H) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 155.1 (dd, J = 251.6, 6.0 Hz), 135.9 (t,
J = 14.0 Hz), 122.7–120.8 (m), 84.3–84.5 (m), 61.7 ppm. 19F NMR
(282 MHz, [D6]DMSO): δ = –127.2 ppm. HRMS: calcd. for
C7H5F2IO 269.9353; found 269.9358. C7H5F2IO (270.02): calcd. C
31.14, H 1.87; found C 31.10, H 1.91.
General Procedure for the Iodination of the Phenols: To a solution
of iodine (1.90 g, 7.5 mmol), potassium iodide (1.25 g, 7.5 mmol)
and the corresponding phenol (5 mmol) in water (25 mL) was
added dropwise a solution of sodium hydroxide (0.4 g, 10 mmol)
in water (25 mL) at 0 °C. The reaction mixture was warmed up to
room temperature and then stirred for 1.5 h. After completion of
the reaction, the mixture was neutralized with ammonium chloride,
followed by addition of sodium thiosulfate until decolorization of
the mixture. The aqueous phase was extracted three times with tert-
butyl methyl ether (10 mL). The combined organic extracts were
washed with brine (15 mL), dried with MgSO4, and the solvent was
removed under reduced pressure. The crude product was purified
either by sublimation, short-path distillation or column chromatog-
raphy, depending on the substrate.
3,4-Difluoro-6-iodophenol (2c): 3,4-Difluorophenol (1c) (1.01 g,
7.76 mmol), iodine (1.97 g, 7.76 mmol), potassium iodide (1.29 g,
7.76 mmol), sodium hydroxide (0.62 g, 15.52 mmol), stirred at 0 °C
for 2 h, purified by column chromatography (toluene, RF = 0.38),
yielded 2c as a colorless liquid (1.75 g, 6.83 mmol, 88%). 1H NMR
(300 MHz, [D6]DMSO): δ = 10.76 (br. s, 1 H, OH), 7.83–7.61 (m,
1 H), 6.95–6.74 (m, 1 H) ppm. 13C NMR (75 MHz, [D6]DMSO):
δ = 153.7 (dd, J = 8.9, 2.2 Hz), 149.4 (dd, J = 245.8, 13.5 Hz),
142.9 (dd, J = 240.3, 13.2 Hz), 126.0 (d, J = 19.8 Hz), 103.2 (d, J
= 19.8 Hz), 77.1 (dd, J = 6.2, 3.6 Hz) ppm. 19F NMR (282 MHz,
General Procedure for the Iodination/Methylation Sequence: The
whole series of reactions starts wih of the phenol substrate 1
(5 mmol). The iodination was carried out as described above. The
crude product was converted without further purification: A mix-
ture of the corresponding iodinated phenol (5 mmol), potassium
carbonate (0.83 g, 6 mmol) and methyl iodide (0.38 mL, 0.85 g,
6 mmol) in DMF (10 mL) was stirred at room temperature for 3 h.
Then ammonia solution (10% in water, 25 mL) was added and the
aqueous phase extracted two times with tert-butyl methyl ether
(10 mL). The combined organic extracts were washed three times
[D6]DMSO):
δ = –136.26, –148.81 ppm. HRMS: calcd. for
C6H3F2IO 255.9197; found 255.9201. C6H3F2IO (255.99): calcd. C
28.15, H 1.18; found C 27.95, H 1.32.
3,4-Difluoro-6-iodoanisole (3c): 3,4-Difluorophenol (1c) (0.79 g,
6.07 mmol), for equiv. of iodination reagents see 2c, purified by
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R. Francke, G. Schnakenburg, S. R. Waldvogel
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column chromatography after step 1 (see 2c) and by short-path
distillation after step 2 (70 °C, 1 mbar) yielded 3c as a colorless
liquid, which crystallized upon standing (1.38 g, 5.11 mmol, 84%).
1H NMR (300 MHz, [D6]DMSO): δ = 7.87 (dd, J = 9.8, 9.1 Hz, 1
H), 7.19 (dd, J = 12.9, 7.0 Hz, 1 H), 3.81 (s, 3 H) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 154.9 (dd, J = 8.1, 2.1 Hz), 149.8 (dd,
J = 245.8, 13.3 Hz), 143.7 (dd, J = 242.1, 13.1 Hz), 126.4 (d, J =
3,4,5-Trifluoro-2,6-diiodophenol (2f): 3,4,5-Trifluorophenol (1e)
(1.00 g, 6.75 mmol), iodine (5.15 g, 20.25 mmol), potassium iodide
(3.36 g, 20.25 mmol), sodium hydroxide (0.81 g, 20.25 mmol), puri-
fied by sublimation (60 °C, 10–2 mbar), yielded 2f as a colorless
solid (2.54 g, 6.35 mmol, 94%); m.p. 81 °C. 1H NMR (300 MHz,
[D6]DMSO): δ = 10.22 (br. s, 1 H, OH) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 152.9 (dd, J = 8.8, 5.7 Hz), 150.3 (ddd, J = 239.9,
19.4 Hz), 101.4 (d, J = 21.8 Hz), 78.6 (dd, J = 6.1, 3.9 Hz), 11.1, 6.4 Hz), 132.4 (dt, J = 248.1, 19.1 Hz), 71.5 (d, J = 26.0 Hz)
57.3 ppm. 19F NMR (282 MHz, [D6]DMSO): ppm. 19F NMR (282 MHz, [D6]DMSO):
δ
=
–135.17, –112.30,
δ
=
–147.12 ppm. HRMS: calcd. for C7H5F2IO 269.9353; found
269.9352. C7H5F2IO (270.02): calcd. C 31.14, H 1.87; found C
31.05, H 1.98.
–165.00 ppm. HRMS: calcd. for C6HF3I2O 399.8069; found
399.8064. C6HF3I2O (399.88): calcd. C 18.02, H 0.25; found C
17.85, H 0.41.
3,4,5-Tifluoro-2,6-diiodoanisole (3f): 3,4,5-Trifluorophenol (1e)
(0.94 g, 6.35 mmol), for equiv. of iodination reagents see 2f, puri-
fied by column chromatography (cyclohexane/ethyl acetate, 99:1,
RF = 0.37) yielded 3f as a colorless solid (2.39 g, 5.78 mmol, 91%);
m.p. 73 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 3.75 (s, 3 H)
ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 155.4 (td, J = 5.3,
3.9 Hz), 150.6 (ddd, J = 242.1, 11.1, 5.9 Hz), 135.2 (dt, J = 253.4,
18.9 Hz), 76.6 (d, J = 25.6 Hz), 60.9 ppm. 19F NMR (282 MHz,
3,4-Difluoro-2,6-diiodophenol (2d): 3,4-Difluorophenol (1c) (1.00 g,
7.69 mmol), iodine (5.85 g, 23.06 mmol), potassium iodide (3.83 g,
23.06 mmol), sodium hydroxide (0.92 g, 23.06 mmol), purified by
sublimation (60 °C, 1 mbar), yielded 2d as a colorless solid (2.79 g,
7.30 mmol, 95%); m.p. 86 °C. 1H NMR (300 MHz, [D6]DMSO): δ
= 9.86 (br. s, 1 H, OH), 7.90 (dd, J = 9.6, 9.1 Hz) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 153.6–153.3 (m), 149.6 (dd, J = 241.4,
14.1 Hz), 143.2 (dd, J = 246.1, 15.9 Hz) 125.7 (d, J = 20.4 Hz),
79.6 (dd, J = 5.9, 3.8 Hz), 77.8 (d, J = 23.0 Hz) ppm. 19F NMR
(282 MHz, [D6]DMSO): δ = –112.94, –143.64 ppm. HRMS: calcd.
for C6H2F2I2O 381.8163; found 381.8164. C6H2F2I2O (381.89):
calcd. C 18.87, H 0.53; found C 18.93, H 0.61.
[D6]DMSO):
δ = –112.15, –159.2 ppm. HRMS: calcd. for
C7H3F3I2O 413.8225; found 413.8222. C7H3F3I2O (413.90): calcd.
C 20.31, H 0.73; found C 20.34, H 0.90.
4-Bromo-2-fluoro-6-iodophenol (2g): 4-Bromo-2-fluorophenol (1g)
(1.00 g, 5.24 mmol), purified by column chromatography (cyclohex-
ane/ethyl acetate, 9:1, RF = 0.33) yielded 2g as a colorless solid
(1.49 g, 4.71 mmol, 90%); m.p. 67 °C. 1H NMR (300 MHz, [D6]-
DMSO): δ = 10.75 (s, 1 H, OH), 7.68 (dd, J = 2.2, 1.8 Hz, 1 H),
7.51 (dd, J = 10.2, 2.3 Hz, 1 H) ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 149.9 (d, J = 247.8 Hz), 144.6 (d, J = 15.3 Hz), 135.61
(d, J = 3.5 Hz), 119.3 (d, J = 22.5 Hz), 110.3 (d, J = 8.9 Hz), 88.4
(d, J = 1.9 Hz) ppm. 19F NMR (282 MHz, [D6]DMSO): δ =
–127.70 ppm. HRMS: calcd. for C6H3BrFIO 315.8396; found
315.8397. C6H3BrFIO (316.89): calcd. C 22.74, H 0.95; found C
22.65, H 1.01.
3,4-Difluoro-2,6-diiodoanisole (3d): 3,4-Difluorophenol (1c) (0.72 g,
5.53 mmol), for equiv. of iodination reagents see 2d, purified by
short-path distillation (75 °C, 10–2 mbar) yielded 3d (1.97 g,
4.98 mmol, 90%) as a colorless solid; m.p. 43 °C. 1H NMR
(300 MHz, [D6]DMSO): δ = 8.07–7.93 (m, 1 H), 3.74 (s, 3 H) ppm.
13C NMR (75 MHz, [D6]DMSO): δ = 156.1 (dd, J = 3.2, 3.2 Hz),
150.0 (dd, J = 243.8, 14.2 Hz), 145.7 (dd, J = 251.2, 15.7 Hz), 126.3
(d, J = 20.0 Hz), 84.3 (dd, J = 5.9, 4.0 Hz), 82.2 (d, J = 22.5 Hz),
60.5 ppm. 19F NMR (282 MHz, [D6]DMSO):
δ = –112.88,
–138.08 ppm. HRMS: calcd. for C7H4F2I2O 395.8320; found
395.8308. C7H4F2I2O (395.91): calcd. C 21.24, H 1.02; found C
21.35, H 1.02.
4-Bromo-2-fluoro-6-iodoanisole (3g): 4-Bromo-2-fluorophenol (1g)
(0.65 g, 3.40 mmol), purified by short-path distillation (65 °C,
10–2 mbar) yielded 3g as a colorless liquid (0.98 g, 2.98 mmol,
3,4,5-Trifluoro-2-iodophenol (2e): 3,4,5-Trifluorophenol (1e) (1.07 g,
7.23 mmol), iodine (1.83 g, 7.23 mmol), potassium iodide (1.20 g,
7.23 mmol), sodium hydroxide (0.58 g, 14.46 mmol), stirred at 0 °C
for 2.5 h, purified by column chromatography (toluene, RF = 0.31),
yielded 2e as a colorless liquid (1.39 g, 5.06 mmol, 70%). 1H NMR
(300 MHz, [D6]DMSO): δ = 11.08 (br. s, 1 H, OH) 6.75 (ddd, J =
12.2, 6.4, 2.3 Hz) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 153.5
(ddd, J = 11.5, 7.2, 2.7 Hz), 150.7 (ddd, J = 238.8, 10.9, 6.3 Hz),
150.3 (ddd, J = 245.1, 10.5, 6.2 Hz) ppm. 132.3 (ddd, J = 242.1,
18.4, 16.3), 98.5 (d, J = 20.3), 69.1 (d, J = 24.4) ppm. 19F NMR
1
87%). H NMR (300 MHz, [D6]DMSO): δ = 7.84–7.76 (m, 1 H),
7.65 (dd, J = 10.7, 2.2 Hz, 1 H), 3.82 (s, 3 H) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 153.9 (d, J = 254.5 Hz), 146.9 (d, J =
1.9 Hz), 136.1 (d, J = 3.6 Hz), 120.7 (d, J = 22.9 Hz), 116.2 (d, J
= 9.3 Hz), 94.2 (d, J = 1.4 Hz), 61.2 ppm. 19F NMR (282 MHz,
[D6]DMSO): δ = –123.97 ppm. HRMS: calcd. for C7H5BrFIO
329.8552; found 329.8550. C7H5BrFIO (330.92): calcd. C 25.41, H
1.52; found C 25.33, H 1.62.
(282 MHz, [D6]DMSO):
HRMS: calcd. for C6H2F3IO 273.9102; found 273.9101. C6H2F3IO
(273.98): calcd. C 26.30, H 0.74; found C 25.95, H 0.77.
δ = –114.13, –135.38, –170.74 ppm.
2,4-Dichloro-6-iodophenol (2h): 2,4-Dichlorophenol (1h) (2.00 g,
12.27 mmol), purified by sublimation (65 °C, 10–1 mbar) yielded 2h
as a colorless solid (3.19 g, 11.04 mmol, 90%); m.p. 62 °C (ref.[23]
1
m.p. 62 °C). H NMR (300 MHz, [D6]DMSO): δ = 10.31 (br. s, 1
3,4,5-Tifluoro-2-iodoanisole (3e): 3,4,5-Trifluorophenol (1e) (0.94 g,
6.32 mmol), for equiv. of iodination reagents see 2e, purified by
column chromatography after step 1 (see 2e) and by short-path
distillation after step 2 (60 °C, 2 mbar) yielded 3e as a colorless
solid (1.20 g, 4.17 mmol, 66%); m.p. 41 °C. 1H NMR (300 MHz,
[D6]DMSO): δ = 7.13 (ddd, J = 12.9, 6.3, 2.3 Hz, 1 H), 3.83 (s, 3
H, OH), 7.73 (d, J = 2.5 Hz, 1 H), 7.54 (d, J = 2.5 Hz, 1 H) ppm.
13C NMR (75 MHz, [D6]DMSO): δ = 151.7, 136.6, 129.2, 124.5,
120.7, 88.7 ppm. HRMS: calcd. for C6H3Cl2IO 287.8606; found
287.8604. C6H3Cl2IO (288.90): calcd. C 24.94, H 1.05; found C
24.98, H 1.08.
H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 154.6–154.3 (m), 2,4-Dichloro-6-iodoanisole (3h): 2,4-Dichlorophenol (1h) (1.25 g,
150.7 (ddd, J = 245.0, 10.3, 5.9 Hz), 150.6 (ddd, J = 244.5, 18.5,
16.3 Hz) ppm. 133.2 (ddd, J = 244.5, 18.5, 16.3), 96.8 (d, J = 22.4),
7.65 mmol), purified by column chromatography (cyclohexane/
ethyl acetate, 99:1, RF = 0.61) yielded 3h as a colorless solid (1.99 g,
70.4 (d, J = 22.9), 57.5 ppm. 19F NMR (282 MHz, [D6]DMSO): 6.58 mmol, 86%); m.p. 36 °C (ref.[24] m.p. 35 °C). 1H NMR
δ = –113.68, –134.17, –168.62 ppm. HRMS: calcd. for C7H4F3IO
287.9259; found 287.9253. C7H4F3IO (288.01): calcd. C 29.19, H
1.40; found C 29.22, H 1.50.
(300 MHz, [D6]DMSO): δ = 7.87 (d, J = 2.5 Hz, 1 H), 7.69 (d, J =
2.5 Hz, 1 H), 3.77 (s, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ
= 154.5, 137.1, 130.1, 129.7, 127.3, 94.3, 60.5 ppm. HRMS: calcd.
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Iodination and O-Methylation of Fluorinated Phenols
for C7H5Cl2IO 301.8762; found 301.8752. C7H5Cl2IO (302.92): 2,3,4-Trifluoro-6-iodoanisole (3k): 2,3,4-Trifluorophenol (1k)
calcd. C 27.75, H 1.66; found C 27.77, H 1.78.
(1.00 g, 6.75 mmol), purified by short-path distillation (55 °C,
2 mbar) yielded 3k as a colorless liquid (1.75 g, 6.08 mmol, 90%).
1H NMR (300 MHz, [D6]DMSO): δ = 7.84 (ddd, J = 9.8, 8.4,
2.6 Hz, 1 H), 3.84 (d, J = 1.2 Hz, 3 H) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 146.7 (ddd, J = 247.7, 10.3, 2.7 Hz), 145.0 (dd, J
= 9.0, 4.1 Hz), 143.8 (ddd, J = 252.7, 10.9, 4.1 Hz), 139.5 (ddd, J
= 250.6, 16.4, 14.0 Hz), 120.5 (dd, J = 19.9, 3.7 Hz), 84.9 (dd, J =
7.6, 4.0 Hz), 61.6 (d, J = 3.9 Hz, OMe) ppm. 19F NMR (282 MHz,
[D6]DMSO): δ = –139.52, –147.53, –156.80 ppm. HRMS: calcd. for
C7H4F3IO 287.9259; found 287.9259. C7H4F3IO (288.01): calcd. C
29.19, H 1.40; found C 29.23, H 1.50.
2-Chloro-4-fluoro-6-iodophenol (2i): 2-Chloro-4-fluorophenol (1i)
(1 g,
6.82 mmol),
purified
by
short-path
distillation
(60 °C,10–2 mbar) yielded 2i as a colorless oil, which solidified upon
standing (1.47 g, 5.39 mmol, 79%); m.p. 37 °C. 1H NMR
(300 MHz, [D6]DMSO): δ = 9.94 (br. s, 1 H, OH), 7.61 (dd, J =
7.7, 3.0 Hz, 1 H) 7.42 (dd, J = 8.3, 3.0 Hz, 1 H) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 155.0 (d, J = 243.3 Hz), 149.3 (d, J =
3.1 Hz), 124.1 (d, J = 24.2 Hz), 120.2 (d, J = 11.2 Hz), 116.8 (d, J
= 25.9 Hz), 87.7 (d, J = 9.2 Hz) ppm. 19F NMR (282 MHz, [D6]-
DMSO):
δ = –121.63 ppm. HRMS: calcd. for C6H3ClFIO
271.8901; found 271.8901. C6H3ClFIO (272.44): calcd. C 26.45, H
1.11; found C 26.47, H 1.16.
2,3-Difluoro-4-iodo-6-nitrophenol (2l): 2,3-Difluoro-6-nitrophenol
(1l) (2.02 g, 11.54 mmol), iodine (5.85 g, 23.08 mmol), potassium
iodide (3.30 g, 23.08 mmol), sodium hydroxide (0.92 g,
23.08 mmol), stirred at 85 °C for 8 h, purified by column
chromatography (short column, cyclohexane/ethyl acetate, 1:1),
yielded 2l as a yellow solid (3.33 g, 10.96 mmol, 95%); m.p. 79 °C.
1H NMR (300 MHz, [D6]DMSO): δ = 7.95 (dd, J = 7.6, 1.8 Hz, 1
H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 157.5 (dd, J = 14.6,
4.7 Hz), 152.6 (dd, J = 249.8, 12.4 Hz), 144.4 (dd, J = 242.8,
10.4 Hz), 136.1 (d, J = 4.9 Hz), 128.9 (dd, J = 5.2, 3.8 Hz), 56.4–
55.7 (m) ppm. 19F NMR (282 MHz, [D6]DMSO): δ = –114.4,
–153.4 ppm. HRMS: calcd. for C6H2F2INO3 300.9047; found
300.9047. C6H2F2INO3 (300.99): calcd. C 23.94, H 0.67, N 4.65;
found C 23.92, H 0.65, N 4.83.
2-Chloro-4-fluoro-6-iodoanisole (3i): 2-Chloro-4-fluorophenol (1i)
(0.47 g, 3.19 mmol), purified by column chromatography (cyclohex-
ane/ethyl acetate, 99:1, RF = 0.44) yielded 3i as a colorless solid
(0.63 g, 2.20 mmol, 69%); m.p. 33 °C. 1H NMR (300 MHz, [D6]-
DMSO): δ = 7.72 (dd, J = 7.7, 3.0 Hz, 1 H) 7.56 (dd, J = 8.3,
3.0 Hz, 1 H), 3.75 (s, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO):
δ = 157.8 (d, J = 248.6 Hz), 152.2 (d, J = 3.6 Hz), 126.7 (d, J =
11.6 Hz), 124.6 (d, J = 24.4 Hz), 117.8 (d, J = 26.2 Hz), 93.3 (d, J
= 9.4 Hz), 60.4 ppm. 19F NMR (282 MHz, [D6]DMSO): δ =
–115.41 ppm. HRMS: calcd. for C7H5ClFIO 285.9058; found
285.9055. C7H5ClFIO (286.47): calcd. C 29.35, H 1.76; found C
29.67, H 1.87.
2,3-Difluoro-4-iodo-6-nitroanisole (3l): 2,3-Difluoro-6-nitrophenol
(1l) (1.39 g, 7.94 mmol), stirred for 3 d, purified by column
chromatography (cyclohexane/toluene, 2:1, RF = 0.38) yielded 3l as
a light yellow solid (2.15 g, 6.83 mmol, 86%); m.p. 46 °C. 1H NMR
(300 MHz, [D6]DMSO): δ = 8.28 (dd, J = 6.0, 2.5 Hz, 1 H), 4.03
(d, J = 2.1 Hz, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ =
153.3 (dd, J = 249.8, 11.9 Hz), 143.6 (dd, J = 255.1, 16.9 Hz), 143.0
(dd, J = 11.5, 2.7 Hz), 140.7–140.5 (m), 128.2 (dd, J = 3.7, 3.7 Hz),
75.9 (dd, J = 25.7, 1.5 Hz), 62.9 (d, J = 5.6 Hz) ppm. 19F NMR
(282 MHz, [D6]DMSO): δ = –107.72, –146.76 ppm. HRMS: calcd.
for C7H4F2INO3 314.9204; found 314.9204. C7H4F2INO3 (315.01):
calcd. C 26.69, H 1.28, N 4.45; found C 26.71, H 1.35, N 4.49.
4-Chloro-2-fluoro-6-iodophenol (2j): 4-Chloro-2-fluorophenol (1j)
(1 g, 6.82 mmol), purified by sublimation (55 °C, 1.2ϫ10–2 mbar)
yielded 2j as a colorless solid (1.78 g, 6.55 mmol, 96%); m.p. 65 °C.
1H NMR (300 MHz, [D6]DMSO): δ = 10.72 (br. s, 1 H, OH), 7.61–
7.53 (m, 1 H) ppm. 7.42 (dd, J = 10.5, 2.5, 1 H) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 149.7 (d, J = 246.8 Hz), 144.3 (d, J =
15.4 Hz), 133.1 (d, J = 3.5 Hz), 123.5 (d, J = 9.6 Hz), 116.7 (d, J
= 22.9 Hz), 87.8 (d, J = 2.3 Hz) ppm. 19F NMR (282 MHz, [D6]-
DMSO):
δ = –127.89 ppm. HRMS: calcd. for C6H3ClFIO
271.8901; found 271.8902. C6H3ClFIO (272.44): calcd. C 26.45, H
1.11; found C 26.17, H 1.12.
4-Chloro-2-fluoro-6-iodoanisole (3j): 4-Chloro-2-fluorophenol (1j)
(0.74 g, 5.06 mmol), purified by column chromatography (cyclohex-
ane/ethyl acetate, 9:1, RF = 0.47) yielded 3j as a colorless liquid
(1.28 g, 4.45 mmol, 88%). 1H NMR (300 MHz, [D6]DMSO): δ =
7.70 (dd, J = 2.4, 1.8 Hz, 1 H), 7.55 (dd, J = 11.0, 2.5 Hz), 3.83 (s,
3 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 153.6 (d, J =
253.3 Hz), 146.5 (d, J = 11.9 Hz), 133.4 (d, J = 3.6 Hz), 128.8 (d,
J = 10.3 Hz), 118.0 (d, J = 23.3 Hz), 93.6 (d, J = 1.7 Hz), 61.2 (d,
4-Fluoro-6-iodo-2-methylphenol (2m): 4-Fluoro-2-methylphenol
(1m) (1.07 g, 8.50 mmol), iodine (2.26 g, 8.92 mmol, 1.05 equiv.),
potassium iodide (1.48 g, 8.92 mmol, 1.05 equiv.), sodium hydrox-
ide (0.68 g, 17.00 mmol, 2 equiv.), purified by sublimation (55 °C,
4 mbar) yielded 2m as a colorless solid (1.27 g, 5.06 mmol, 64%);
m.p. 57 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 8.94 (s, 1 H,
OH), 7.42–7.31 (m, 1 H), 7.00 (ddd, J = 9.1, 3.1, 0.6 Hz, 1 H), 2.21
(s, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 155.9 (d, J =
239.6 Hz), 151.1 (d, J = 2.4 Hz), 127.1 (d, J = 8.0 Hz), 122.0 (d, J
= 24.3 Hz), 117.1 (d, J = 22.3 Hz), 87.0 (d, J = 9.0 Hz), 17.5 (d, J =
1.3 Hz) ppm. 19F NMR (282 MHz, [D6]DMSO): δ = –123.46 ppm.
HRMS: calcd. for C7H6FIO 251.9447; found 251.9456. C7H6FIO
(252.02): calcd. C 33.36, H 2.40; found C 33.31, H 2.68.
J
= δ =
4.7 Hz) ppm. 19F NMR (282 MHz, [D6]DMSO):
–124.12 ppm. HRMS calcd. for C7H5ClFIO 285.9058; found
285.9055. C7H5ClFIO (286.47): calcd. C 29.35, H 1.76; found C
29.75, H 1.91.
2,3,4-Trifluoro-6-iodophenol (2k): 2,3,4-Trifluorophenol (1k) (1 g,
6.75 mmol), purified by short-path distillation (60 °C, 2 mbar)
yielded 2k as a colorless liquid which solidified upon standing
(1.76 g, 6.42 mmol, 95%); m.p. 37 °C. 1H NMR (300 MHz, [D6]-
DMSO): δ = 10.91 (br. s, 1 H, OH), 7.71 (ddd, J = 9.9, 8.5, 2.6 Hz,
1 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 143.7 (ddd, J =
242.4, 10.5, 2.3 Hz), 142.7 (dd, J = 12.2, 2.8 Hz), 139.7 (ddd, J =
248.4, 11.4, 3.8 Hz), 139.5 (ddd, J = 248.4, 16.4, 14.0 Hz), 120.0
(dd, J = 19.7, 3.6 Hz), 79.4 (dd, J = 7.3, 4.3 Hz) ppm. 19F NMR
4-Fluoro-6-iodo-2-methylanisole (3m): 4-Fluoro-2-methylphenol
(1m) (1.00 g, 7.94 mmol), for equiv. of iodination reagents see 2m,
purified by short-path distillation (60 °C, 3 mbar) yielded 3m as
a colorless liquid (1.16 g, 4.37 mmol, 55%). 1H NMR (300 MHz,
CDCl3): δ = 7.29 (ddd, J = 7.5, 3.0, 0.5 Hz, 1 H), 6.86 (ddd, J =
8.7, 3.0, 0.7 Hz, 1 H), 3.72 (s, 3 H), 2.31 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 158.7 (d, J = 247.0 Hz), 154.7 (d, J =
3.6 Hz), 133.3 (d, J = 8.3 Hz), 123.6 (d, J = 24.9 Hz), 118.1 (d, J
= 22.3 Hz), 91.2 (d, J = 9.5 Hz), 60.6 (s), 17.4 (d, J = 1.5 Hz) ppm.
19F NMR (282 MHz, CDCl3): δ = –118.22 ppm. HRMS: calcd. for
(282 MHz, [D6]DMSO):
δ = –146.17, –151.55, –158.42 ppm.
HRMS: calcd. for C6H2F3IO 273.9102; found 273.9102. C6H2F3IO
(273.98): calcd. C 26.30, H 0.74; found C 26.15, H 0.98.
Eur. J. Org. Chem. 2010, 2357–2362
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R. Francke, G. Schnakenburg, S. R. Waldvogel
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Published Online: March 15, 2010
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 2357–2362